This invention relates to methods for the modification of the lipid structure of cell membranes, to pharmaceutical compositions and methods for their administration and medicaments for use in the methods of the invention, to certain compounds and their derivatives for use in the treatment of disorders, and also relates inter alia to methods for the diagnosis and treatment of malignancy. The invention further relates to methods of treatment, both veterinary and clinical, based on the said compositions and medicaments.
There is a wide range of naturally occurring saturated and unsaturated fatty acids. These generally have an even number of carbon atoms in the chain. The C18 acids (for example stearic, oleic, linoleic and linolenic acids) are well known. Stearic acid is used as a lubricant in making compressed tablets and as an enteric coating for pills and tablets. The acid and its salts are well known as excipients in pharmaceutical formulations. It has also been used, when partly neutralised with alkalis or triethanolamine, as the basis of cosmetic preparations such as vanishing creams. It seems that the C12-C28 saturated fatty acids, e.g. stearic acid, were not hitherto known to have medicinal properties per se.
Both the physical stability of cell membranes and the regulation of a wide variety of metabolic processes, especially those involving membrane-associated enzymes, are dependent on the regulation of cell membrane lipid composition (Sandermann, H, Jr., (1978) Biochim. Biophys. Acta, 515, 209-237). This regulation provides for the homeostasis of membrane fluidity, predominantly through the balance between constituent saturated and unsaturated fatty acids (Doi, O; Doi, F; Schroeder, F; Alberts, A. W & Vagelos, P. R. (1978) Biochim. Biophys. Acta, 509, 239-250; and Quinn, P. J. (1983) Biochem. Soc. Trans. 11, 329-330). Analysis of cell membrane lipids shows that the most abundant species of fatty acids are the 18 carbon (C18) straight chain fatty acids of which the polyunsaturates (e.g. linoleic and linolenic) acids are derived from the diet. Further, the other main components of this family, octadecanoic acid (stearic acid) and cis-9-octadecenoic acid (oleic acid), differ widely in their melting points and so the relative proportions of these acids within the membrane is important in determining membrane fluidity. In normal resting cells, the degree of cell membrane fluidity appears to be associated with the rate of cell division, higher fluidity reflecting a higher rate of division, and vice versa. The enzyme .DELTA.-9 desaturase is involved in the change from saturated to unsaturated fatty acids (Jeffcoat, R. and James, A. T. in New Comprehensive Biochemistry, publ. Elsevier, 1984, vol. 7, pp 85-112). Under normal circumstances the activity of this enzyme is regulated in accordance with requirements of the cell to produce more oleic acid in order to maintain a specific level of membrane fluidity. For convenience, the enzyme .DELTA.-9 desaturase will be referred to as D9DS in the description which follows.